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Why Amarin Has To Finish Its Big Fish Oil Study

When a panel of experts appointed by the Food and Drug Administration said the agency should deny Amarin Pharmaceuticals a broader marketing approval for its fish oil pill Vascepa on Wednesday, the company’s shares tanked 60%, making it the worst-performing biotechnology stock on the Nasdaq or New York Stock Exchange last week. The company reacted with shock and many of its investors became angry.

One idea that came up almost immediately: Amarin should drop the big and expensive study it had started to prove that taking Vascepa to lower triglyceride levels really does prevent heart attacks, strokes, and surgical procedures. Stopping the trial, called REDUCE-IT, was one of the first ideas that analysts brought up on the conference call that followed Amarin’s rout at the FDA. And Joseph S. Zakrzewski, Amarin’s chief executive, refused to rule it out. “We’ve been planning and hopeful of a positive meeting today. But as I said earlier, we’re going to take a look from top to bottom and look at everything.”

I responded on Twitter.

. @adamfeuerstein If they stop Reduce-It, they should close the company and none of the executives should ever work in biotech again. $AMRN

After that, I spent a lot of time arguing with Amarin investors who thought that ending the study was a splendid idea – after all, it is costing Amarin, which has $270 million in the bank, $30 million to $40 million a year and will last until at least 2016, although costs will decrease with time. Amarin had expected REDUCE-IT to be funded by Vascepa sales, which may not come. Why not double down on expanding the sales force instead? Brian Orelli at The Motley Fool accused me of forgetting that a company’s primary duty is to its shareholders, not to science.

The investors and Orelli are not remembering their Pharma history. Stopping REDUCE-IT, which could be the first study to show that a fish oil pill is worth taking, would be considered unethical by many of the doctors who conduct clinical trials and whose endorsement the company needs. It could create bad press that would make Vascepa even harder to sell, be seen as a vote of no confidence by Amarin in its own drug, and remove a huge potential upside for Vascepa sales. In short, it would be both wrong and commercially stupid.

This was back in 2003, and the study was stopped by Pharmacia, when it was being run by Fred Hassan. The study, called CONVINCE, tested a blood pressure medicine called verapamil against standard blood pressure drugs. The study had recruited 16,600 patients, and was supposed to continue until patients had 2,246 heart attacks, strokes, or heart-related deaths.

Instead, Pharmacia stopped the trial two years early “for commercial reasons,” when there had been 729 heart attacks, strokes, or heart related deaths. The independent scientists running the study were told that the study was stopped for “business considerations.” In other words, even though the patients had volunteered, the company did not want to continue to fund the study.

But the JAMA authors argued that stopping studies for business reasons is wrong:

In a capitalist society, legal contracts permitting, companies can fire employees, decline to purchase components or equipment, and even cancel some consulting or research arrangements with scientists. But the recruitment and involvement of human research participants places clinical trials in a category decidedly distinct from the customary swapping and trading of ordinary goods and services. When patients or other research participants are recruited for scientific investigations, they agree willingly to expose themselves to risk. Individuals often participate out of a sense of altruism, and counted among the most important reasons for joining trials are the improvements in their own health, the contributions to science, and the improvement of the health of others.

They further argue that stopping trials early represents a violation of the Declaration of Helsinki, used as an ethical guide for medical experiments. It’s wrong to ask patients to enroll in a study that is too small to have a chance at delivering an answer. So isn’t it also wrong to shrink a study that was big enough by stopping it early?

There’s room for disagreement here; Psaty and Rennie cite other articles that argue it is perfectly ethical for companies to stop trials to deploy limited resources. But the anger many investors feel against the FDA doesn’t matter to those arguments; the idea is that there is a contract between Amarin and patients, not between Amarin and the FDA. At the very least, stopping the study is likely to weaken Amarin’s commercial case in the meantime. The company really has no choice but to dig in its heels and wait for the REDUCE-IT results in three years.

I reached out to a public relations person retained by Amarin about this story and did not receive a response.

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Hey Matt, tell it to the FDA. Amarin doesn’t have an obligation to go bankrupt. I would love to see Red-it go the distance, but if the money to do so isn’t there, Amarin will have to go LEAN to survive on the Marine indication.

I suspect there are plenty of folks behind BP whom would have no issue with Amarin going belly up. They would rather the masses spend their money on their post illness treatments rather than Amarins preventitive medicine.

You must be living on an inheritance or something, or you don’t understand basic math. The REDUCE-IT trial was an explicit “quid pro quo” baked into the SPA between the FDA and Amarin. If the FDA had been explicit up-front about its intentions, Amarin would never have, and could never have, agreed to the SPA. There is no reasonable way to fund the REDUCE-IT study otherwise.

The FDA is moronic beyond comprehension (a defensible thesis), or simply sinister, if they attempt to claim they didn’t understand that the completion of the REDUCE-IT trial was contingent on approval of the ANCHOR indication (presuming, of course, that it met its endpoints, which it did on all counts).

The FDA claims that “the science has changed” but there is evidence on both sides, and the directly relevant evidence — on EPA — is all in favor of Vascepa. The FDA decided to emphasize the barely relevant stuff, and ignore the directly relevant part. Because, of course, they had their minds made up before the “review” began.

The moral imperative here is two-sided, and contingent on the first party satisfying its obligations so the second one reasonably can do the same. As one of the AdCom panelists stated, “They’ve done everything you asked them to do.”

This is classic Big Brother boot-on-the-head no-accountability SOP. It’s one thing to say, “Well, that’s the FDA. They do what they do, and you have to live with it.” It’s another thing to claim that the party destroyed by a bureaucratic leviathan has a moral expectation on its back now, while Big Brother cracks open a cold one.

Where do you get the idea that REDUCE-IT was an explicit quid pro quo? Did Amarin ever say this?

Here is the guidance on SPAs from FDA and the goals for SPAs, also from FDA. It’s pretty clear that an SPA is not an ironclad promise to approve a drug. The FDA doesn’t agree to anything. It looks at the study and tells you if it saw issues.

But the moral imperative is not between FDA and Amarin. It’s between Amarin and the patients who have donated their bodies to proving its medicine works.

I’m sorry, I’m having a little trouble hearing you all the way up there on your exaggerated moral pedestal.

If it were possbile for Amarin to reasonably fund the outcome study without the additional indication, the SPA would not have been structured the way it was. It is obvious TO EVERYONE, including the FDA, that the structure of the SPA implies, implicitly, that funds from sales of Vascepa from the expanded indication will permit the REDUCE-IT trial to be paid for and completed. Who writes “quid pro quo” in legal documents, or says it in a public forum? Come on.

Spare us all the “donated bodies” moralizing. This isn’t a Stage IV cancer trial — it’s an add-on supplement to statin therapy to get trigs down and improve long-term CV outcomes. Nobody is being jeopardized by having this trial stop. Everyone on this trial could go to their doctor 5 minutes after the trial closed and say, “Can you prescribe me Vascepa?” It’s on the market already, and can perfectly well be prescribed off-label — just like Lovaza. There is literally no moral impact at the individual level.

I would agree that everyone is better off if this trial is completed, because the general science of connecting trig reduction with improved CV outcomes would advance. But the FDA is not allowed to treat entrepreneurs like host organisms that they can latch onto and suck dry like a tick. There was obvious mutuality in this agreement, the FDA appears to be on the verge of violently breaching that agreement — perhaps not strictly legally, but certainly in the realm of reasonableness and honesty — and Amarin is not required to bankrupt itself to fund the study. If the government desperately wants the study done, and they won’t honor their SPA, they can freaking pay for it.

This government has already blown more than $5 trillion in the last 5 years in exchange for next to nothing. What’s a couple hundred million more to actually get something useful?

The moral imperative is with the FDA and the patients, that is why we have this government agency. Remember it was FDA who expanded the label on the application to include statins and to ascertain CV events. The company can survive as a better alternative to Lovaza building a business off label like Lovaza to include statins from doctors who are knowledgeable enough to prescribe it. Without FDA approval on Dec. 20 Reduce it only has a potential downside, financially and with the burden of a negative outcome. If the FDA is concerned about the 36 million sick CV patients then they need to approve anchor on December 20. It would be nice to see a Forbes business writer to take on the FDA on this issue not investors who have skin in the game or the company who is just trying to build a profitable business. I hope your not writing your article to help the short sellers on a day that the stock is up 13%.

Again FDA changed the SPA application to expand label coverage to include statins. Original submission only had expand label for Trigs between 200 to 500 mg/dl. It did not include combination with statin.